Normal function of the airway tree is to permit the free flow of gas to and from the alveoli. The lung is unique among organs, in that it is continually subjected to small dynamic stresses associated with ventilation, and periodically subjected to more substantial stresses associated with sighs or deep inspirations. Although these factors have been studied by many investigators for several years, the focus of the present application will be to examine in a programmatic fashion the effects on the three most important components of the lung, the airways, the parenchyma, and the vasculature. As will be apparent in the written application, this sharper programmatic focus is a direct outgrowth of the work that has been funded for the past four years, as well as collaborative interactions that have developed outside of the PPG. The new PPG will now be focused on functional and pathological manifestations of lung distension that may lead to severe difficulty in breathing or even death. Although many of these factors have been well studied independently, how they interact remains poorly understood. Of the many possible factors and processes that might be involved in this interaction of parenchyma and airways, this program will focus on those for which preliminary data has suggested are most important, including the physical interaction between contracted parenchyma and airways, the genetic regulation of the structural changes in airways and parenchyma, and the regulation of inflammatory cell traffic by the bronchial circulation. Each project in this program will focus on one or more of these factors in addressing several focused specific aims. Projects and methods span the range from subcellular, molecular, and genetic approaches to quantitative measurements of airway size in vivo in dogs and humans. This tightly integrated program will thereby provide new insights into how airways and parenchyma function in normal and pathologic dynamic environments.